a phase i/ii study to investigate the use of voraxaze™ as intended intervention in patients with cnsl

Conditions: CNS Lymphoma

Summary: this phase i-ii trial is intented to demonstrate tolerability (i.e. absence of severe non-hematological toxicity) and efficacy of intended intervention with repeated doses of voraxaze, in addition to leucovorin (lv), in patients with renal impairment or renal failure during previous hd-mtx therapy. patients will receive up to 6 cycles of hd-mtx treatment with 14 days between cycles (a maximum delay of 28 days is permitted in order to allow time for a patient to recover from the previous cycle).

mtx is used either alone or as part of a combined chemotherapy protocol either in standard or high doses in the treatment of a range of cancers and other diseases. dose escalation will be performed using three dose levels of mtx: level 1: 3.0 g/m2 level 2: 3.5 g/m2 level 3: 4.0 g/m2 up to 6 patients will be treated at each dose level; each will receive a maximum of 6 cycles of treatment. the dose may be increased in cycle 3 in individual patients to the next level, if renal function is adequate (gfr ≥ 40 ml/min, or in the case of decreased gfr, the decrease is \<10% compared with the pre-treatment value), and absence of grade 3 or 4 non-hematological toxicities.

Eligibility criteria:
inclusion criteria: * primary or secondary cnsl (pcnsl or scnsl) confirmed by histology or cytology. * renal insufficiency defined as a glomerular filtration rate (gfr, assessed by ckd-epi or mdrd equation) of 40-80 ml/min or patients with a gfr \>80ml/min who have experienced renal failure, defined as doubling of the serum creatinine compared to the baseline value during a previous hd-mtx treatment. * age ≥ 18 years (male or female). * life expectancy \>3 months. * adequate organ function (i.e., bone marrow, liver, lungs) allowing intensive chemotherapy with mtx. * adequate clinical pathology values: * absolute neutrophil count ≥1.0 x 109/l, hemoglobin ≥9mg/dl (transfusion allowed), platelets ≥100 x 109/l. * total bilirubin ≤1.5x the upper limit of normal except for patients with known gilbert syndrome. * alanine amino-transferase (alt) and aspartate amino-transferase (ast) ≤2x the upper limit of normal. * alkaline phosphatase ≤2x the upper limit of normal. * prothrombin time within the normal range for the institution. * signed informed consent by the patient or legal representative prior to start of any study specific procedure. * females of childbearing potential and males must be willing and able to use an adequate method of contraception to avoid pregnancy for the duration of the study in such a manner that the risk of pregnancy is minimized. acceptable contraceptives include intra-uterine devices (iuds), hormonal contraceptives (oral, depot, patch or injectable) and double barrier methods such as condoms or diaphragms with spermicidal gel or foam. exclusion criteria: * ongoing or expected need for therapy with drugs interfering with mtx-clearance (i.e., beta-lactam antibiotics, nsaids, probenicid, salicylates, sulphonamides) or other nephrotoxic drugs. * prior brain radiotherapy within 28 days of first dose of the study drug. * concurrent illness interfering with hydration (i.e., relevant congestive heart failure, siadh syndrome). * relevant third space (i.e., pleural effusion, ascites, extended edema) precluding hd-mtx treatment. * obesity (body mass index \>30 kg/m2). * uncontrolled diabetes. * active hepatitis. * hiv-infection. * pregnant or lactating woman. * participation in any other clinical trial either 1 month prior to or during this study. * previous intolerance to any of the drugs used in this study (i.e., mtx, lv)

Keywords: impaired renal function